It has been reported that approximately half of American adults aged 30 years and older have periodontitis, and the prevalence of periodontitis further increase in aged populations and in patients with diabetes or that smoke (Eke et al., 2012; Papapanou and Tonetti, 2000). Approximately 50% of periodontitis patients aged 30 years and older have alveolar bone loss that eventually may lead to tooth loss and osseointegration failure of dental implants if patients do not receive efficient therapeutics to arrest the progression of this chronic disease (Papapanou and Tonetti, 2000). Although anti-resorptive and anabolic agents, including vitamin D, calcium, hormone replacements, and bisphosphonates, are currently used to prevent and treat systemic osteoporosis, the efficacy of these treatments in arresting periodontal bone loss and improving osseointegration of dental implants has not been confirmed (Armas et al., 2013; Jeffcoat, 1998; Sidiropoulou-Chatzigiannis, 2007). Long-term use of intravenous bisphosphonates has been shown to cause osteonecrosis of jaws (Khosla et al., 2012).
While bacteria derived factors initiate periodontitis, there is strong evidence that the majority of periodontitis occurs due to activation of host-derived immune and inflammatory defense mechanisms. Toll-like receptors (TLRs) are the major cell-surface initiators of inflammatory responses to pathogens. TLR-2 and TLR-4 have been demonstrated to play critical roles in recognizing periodontal pathogens and trigger the up-regulation of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in periodontitis (Darveau, 2010; DiBenedetto et al., 2013). TLR-mediated signaling pathways also lead to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key proinflammatory transcription factor (Herath at al., 2013). These cytokines and transcription factors in turn further amplify the inflammatory response and lead to production of lytic enzymes and stimulate the production of chemokines, including IL-6, IL-8 and CCL-5 (Darveau et al., Di Benedetto at al., 2013; Kajishengallis et al., 2012). Eventually, a cascade of events leads to osteoclastogenesis and subsequent bone resorption via the receptor activator of nuclear factor kappa-B ligand (RANKL)-osteoprotegerin (OPG) axis. Thus, imbalance and dysregulation of proinflammatory molecules and cytokine networks play essential roles in the process of periodontitis and associated bone resorption (Darveau, 2010; Di Benedetto at al., 2013). Reducing the expression and activation of proinflammatory and bone metabolism mediators that activate osteoclastogenesis and bone resorption may serve as an effective strategy for preventing and arresting the development of periodontal bone loss. In addition, proinflammatory mediators have been demonstrated to impair bone formation by reducing differentiation of osteoblasts and their progenitor cells (Yang et al., 2013; Lacey et al., 2009; Hikiji et al., 2000; Wang et al., 2012). Specifically, TNF-α and IL-1β have been demonstrated to inhibit osteogenic differentiation of bone marrow stem cells. TNF-α also have been reported to inhibit Osterix expression and promote degradation of Runx2. TNF-α and IL-17 activate IκB kinase (IKK)—NF-κB to reduce osteogenic differentiation of MSCs by promoting β-catenin degradation and impair bone formation. Thus, inhibiting proinflammatory mediators may prevent and restore periodontitis-associated bone loss by increasing osteogenic differentiation and bone formation.